The long-term objective of this project is to understand mechanisms of tumor response to cytotoxic chemotherapy. We will examine the hypothesis that hypoxia inducible factor genes play key roles in determining tumor responses to cytotoxic cancer therapy. We will conduct experiments to characterize cytotoxic chemotherapy-induced HIF-1 and HIF-2 gene activation in murine tumor models using novel molecular imaging approaches. We will examine the roles of specific nitric oxide synthase genes in chemotherapy (cyclophosphamide and etoposide)- induced HIF-1&2 activation (Specific aim 1). We will also make efforts to define the molecular mechanism through which nitric oxide mediates therapy-induced HIF-1&2 activation in cytotoxic chemotherapy therapy (Specific aim 2). In addition, we will evaluate the roles of HIF genes in cancer response to chemotherapy the genetic approaches (Specific Aim 3).